A shape-shifting protein explains rabies’ deadly power

• Viruses are highly efficient, able to take over our cells and control vital processes using a small number of genes.
• For years, scientists have wondered how something so small can do so much.
• Now researchers have revealed the answer, a discovery that could reshape our understanding of how viruses work and lead to new ways to combat them.

Breakthrough reveals how viruses outsmart human cells

A team of Australian scientists has discovered how some viruses are able to take over human cells, a discovery that could lead to the next generation of antiviral drugs and vaccines.

The research was led by Monash University and the University of Melbourne and published in Nature CommunicationsExplains how the rabies virus can manipulate a wide range of cellular activities despite producing only a few proteins.

Scientists believe this same mechanism could also be at work in other deadly pathogens, including the Nipah and Ebola viruses. If so, this discovery could pave the way for new treatments that block these viral strategies.

How viruses do so much with so little

Co-senior author Professor Greg Mosley, head of the Monash Biomedical Institute’s (BDI) Viral Pathology Laboratory, described the remarkable efficiency of viruses.

Professor Mosley said: “Viruses such as rabies can be incredibly deadly because they take over many aspects of life within the cells they infect.” “They hijack the machinery that makes proteins, disrupt the ‘postal service’ that sends messages between different parts of the cell, and disable the defenses that normally protect us from infection.”

He explained that scientists have long puzzled over how viruses with limited genetic material can be so powerful. He added: “The rabies virus, for example, has the genetic material necessary to make only five proteins, compared to about 20,000 proteins in a human cell.”

Key: a shape-shifting viral protein

Co-first author Dr Stephen Rawlinson, a research fellow in Moseley’s lab, said the team’s work provides a long-awaited answer.

“Our study provides an answer,” he said. “We discovered that one of the key proteins of the rabies virus, called the P protein, acquires a remarkable set of functions through its ability to change shape and bind to RNA.”

“RNA is the same molecule used in the new generation of RNA vaccines, but it plays essential roles inside our cells, carrying genetic messages, coordinating immune responses, and helping to form the building blocks of life.”

Control the inner world of the cell

Co-senior author Professor Paul Jolly, who leads Jolly’s laboratory at the University of Melbourne, said the ability of the viral P protein to interact with RNA allows it to switch between different physical “stages” within the cell.

Professor Jolly said: “This allows it to infiltrate many of the fluid-like parts of the cell, take control of vital processes, and turn the cell into a highly efficient virus factory.”

Although this research focused on rabies, it indicated that similar methods could be used by other deadly viruses, including Nipah and Ebola. He added: “Understanding this new mechanism opens up exciting possibilities for developing antivirals or vaccines that inhibit this remarkable ability to adapt.”

Rethinking how viral proteins work

Dr Rawlinson said the findings challenge the way scientists traditionally view multi-functional viral proteins. “Until now, these proteins have often been viewed as trains made up of several cars, with each car (or unit) responsible for a specific task,” he said.

“According to this view, shorter versions of the protein should simply lose their functions when the carts are removed. However, this simple model cannot explain why some shorter viral proteins actually acquire new capabilities. We have found that multiple functions can also arise from the way the ‘carts’ interact and fold together to form different general conformations, as well as creating new abilities such as binding to RNA.”

A new perspective on viral adaptability

Associate Professor Moseley said the P protein’s ability to bind RNA allows it to move between different physical ‘stages’ within the cell.

“By doing this, it can access and manipulate many of the fluid-like parts of the cell that control key processes, such as immune defense and protein production,” he said. “By revealing this new mechanism, our study provides a new way of thinking about how viruses use their limited genetic material to create flexible and adaptable proteins capable of controlling complex cellular systems.”

Monash University, the University of Melbourne, the Australian Synchrotron, the Peter Doherty Institute of Infection and Immunity, the Commonwealth Scientific and Industrial Research Organization (CSIRO), the Australian Center for Disease Preparedness (ACDP) and Deakin University participated in this study.